Syntheses of Melatonin and its Derivatives
Masanori Somei, Yoshikazu Fukui, Masakazu Hasegawa, Naoki Oshikiri, and Toshikatsu Hayashi
Heterocycles 53(8), 1725-1736 (2000) (http://www.heterocycles.jp/data/pdffiles/COM-00-8930.pdf)
(http://www.heterocycles.jp/data/pdffiles/COM-00-8930.pdf)
Abstract: Two simple synthetic methods for melatonin are newly developed from tryptamine through intermediates, which are promising lead compounds for drug developing research. Novel chemical reactivities of melatonin in its bromination, lithiation, and acylation are also reported.
Experimental
N b-Methoxycarbonyl-2,3-dihydrotryptamine (4b) from N b-Methoxycarbonyltryptamine (3b)
Et3SiH (7.50 mL, 46.9 mmol) was added to a solution of 3b (5.03g, 23.0 mmol) in
CF3COOH (100 mL) and the mixture was heated at 60°C for 3 h with stirring. After evaporation of the solvent, H2O was added to the residue. The whole was made basic by adding 2N aqueous NaOH under ice cooling and extracted with CHCl3-MeOH (95:5, v/v). The extract was washed with brine, dried over Na2SO4, and evaporated under reduced pressure to leave an oil, which was column-chromatographed on SiO2 with CHCl3-MeOH (95:5, v/v) to give 4b (4.93g, 97%). 4b: mp 64-65°C (colorless prisms, recrystallized from AcOEt-hexane).
N b-Methoxycarbonyl-1-hydroxytryptamine (5b) from 4b
30% Aq. H2O2 (1.0 mL, 9.18 mmol) was added to a solution of 4b (201.9mg, 0.92 mmol) and Na2WO4×2H2O (63.2mg, 0.18 mmol) in MeOH-H2O (1:1, v/v, 22.0 mL) at 0°C with stirring. Stirring was continued at rt for 30 min and then the whole was extracted with CHCl3. The extract was washed with brine, dried over Na2SO4, and evaporated under reduced pressure to leave an oil, which was column-chromatographed on SiO2 with AcOEt-hexane (1:2, v/v) to give 5b (237.4mg, 65%). 5b: mp 114—115°C (colorless needles, recrystallized from CH2Cl2-hexane).
5-Methoxy-N b-methoxycarbonyltryptamine (6) from 5b
50% BF3-methanol complex (180.0 mL) was added to a solution of 5b (9.64g, 41.2 mmol) in MeOH (500 mL) and the mixture was refluxed for 30 min with stirring. After addition of ice and H2O, the whole was made neutral by adding 40% aq. NaOH and extracted with CHCl3. The extract was washed with brine, dried over Na2SO4, and evaporated under reduced pressure to leave an oil, which was column-chromatographed on SiO2 with CHCl3 to give 6 (8.52g, 83%).
5-Methoxytryptamine (7) from 6
20% Aq. NaOH (1.0 mL) was added to a solution of 6 (51.2 mg, 0.20 mmol) in MeOH (1.0 mL) and the mixture was refluxed for 4 h with stirring. After addition of ice and H2O, the whole was extracted with CHCl3-MeOH (95:5, v/v). The extract was washed with brine, dried over Na2SO4, and evaporated under reduced pressure to leave an oil, which was column-chromatographed on SiO2 with CHCl3-MeOH-28% aq. NH3 (46:5:0.5, v/v) to give 7 (38.8 mg, 99%). 7: mp 124-126°C (lit.,4f mp 120°C, colorless prisms, recrystallized from CHCl3-hexane).
Melatonin (1) from 7
Ac2O (3.0 mL, 31.7 mmol) was added to a solution of 7 (918.0mg, 4.83 mmol) in pyridine (6.0 mL) and the mixture was stirred at rt for 40 min. After evaporation of the solvent under reduced pressure, the whole was made alkaline by adding 2N aq. NaOH under ice cooling and extracted with CHCl3-MeOH (95:5, v/v). The extract was washed with brine, dried over Na2SO4, and evaporated under reduced pressure to leave an oil, which was column-chromatographed on SiO2 with CHCl3-MeOH (99:1, v/v) to give 1 (1.03g, 92%).
Synthesis of 5-Substituted Indole Derivatives. I. An Improved Method for the Synthesis of Sumatriptan
Béla Pete, István Bitter, Csaba Szántay, Jr. , István Schön and László Töke
Heterocycles 48(6), 1139-1149 (1998) (https://www.thevespiary.org/rhodium/Rhodium/pdf/sumatriptan.fischer.pdf)
(https://www.thevespiary.org/rhodium/Rhodium/pdf/sumatriptan.fischer.pdf)
Abstract
An improved synthesis of sumatriptan (1b) via Fischer cyclization was achieved by introducing the ethoxycarbonyl group on the N-atom of the sulphonamide moiety in N-methyl-4-hydrazinobenzenemethanesulphonamide (7). As a result, substitution on the benzylic carbon of the indole nucleus could be avoided; however, formation of 1,1-bis-(indol-2-yl)-4-dimethylaminobutane-type by-product (19) was observed. The indolization procedure was optimized to suppress the unwanted side reaction. The N-protection of the sulphonamide moiety was found to be beneficial regarding the purification of the 3-[2-(dimethylamino)ethyl]-N-ethoxycarbonyl-N-methyl-1H-indole-5-methanesulphonamide (18).